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HIGHLIGHTS OF PRESCRIBING INFORMATION • Elevated blood pressure and heart rate: Cases have
These highlights do not include all the information been reported with Savella. Monitor blood pressure and
needed to use Savella safely and effectively. See full heart rate prior to initiating treatment with Savella and
prescribing information for Savella. periodically throughout treatment (5.3, 5.4)
Savella (milnacipran HCl) Tablets • Seizures: Cases have been reported with Savella
Initial U.S. Approval: 2009 therapy. Prescribe Savella with care in patients with a
history of seizure disorder (5.5)
WARNING: SUICIDALITY AND ANTIDEPRESSANT • Hepatotoxicity: More patients treated with Savella than
DRUGS with placebo experienced mild elevations of ALT and
See full prescribing information for complete boxed AST. Rarely, fulminant hepatitis has been reported in
warning. patients treated with Savella. Avoid concomitant use of
• Increased risk of suicidal ideation, thinking and Savella in patients with substantial alcohol use or
behavior in children, adolescents, and young adults chronic liver disease (5.6)
taking antidepressants for major depressive • Discontinuation: Withdrawal symptoms have been
disorder (MDD) and other psychiatric disorders. reported in patients when discontinuing treatment with
Savella is not approved for use in pediatric patients Savella. A gradual dose reduction is recommended
(5.1) (5.7)
• Abnormal Bleeding: Savella may increase the risk of
---------------------INDICATIONS AND USAGE--------------------- bleeding events. Caution patients about the risk of
Savella™ is a selective serotonin and norepinephrine bleeding associated with the concomitant use of
reuptake inhibitor (SNRI) indicated for the management of Savella and NSAIDs, aspirin, or other drugs that affect
fibromyalgia (1) coagulation (5.9)
Savella is not approved for use in pediatric patients (5.1) • Male patients with a history of obstructive uropathies
may experience higher rates of genitourinary adverse
-----------------DOSAGE AND ADMINISTRATION---------------- events (5.11)
• Administer Savella in two divided doses per day (2.1)
• Begin dosing at 12.5 mg on the first day and increase to -------------------------ADVERSE REACTIONS-----------------------
100 mg/day over a 1-week period (2.1): The most frequently occurring adverse reactions (≥ 5%
Day 1: 12.5 mg once and greater than placebo) were nausea, headache,
Days 2-3: 25 mg/day (12.5 mg twice daily) constipation, dizziness, insomnia, hot flush, hyperhidrosis,
Days 4-7: 50 mg/day (25 mg twice daily) vomiting, palpitations, heart rate increased, dry mouth,
After Day 7: 100 mg/day (50 mg twice daily) and hypertension (6.3)
• Recommended dose is 100 mg/day (2.1)
• May be increased to 200 mg/day based on individual To report SUSPECTED ADVERSE REACTIONS, contact
patient response (2.1) Forest Pharmaceuticals, Inc., at (800) 678-1605 or FDA
• Dose should be adjusted in patients with severe renal at 1-800-FDA-1088 or www.fda.gov/medwatch.
impairment (2.2)
------------------------DRUG INTERACTIONS------------------------
--------------DOSAGE FORMS AND STRENGTHS--------------- • Savella is unlikely to be involved in clinically significant
• Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg (3) pharmacokinetic drug interactions (7)
• Pharmacodynamic interactions of Savella with other
------------------------CONTRAINDICATIONS------------------------ drugs can occur (7)
• Use of monoamine oxidase inhibitors concomitantly or
in close temporal proximity (4.1) ----------------USE IN SPECIFIC POPULATIONS-----------------
• Use in patients with uncontrolled narrow-angle • Pregnancy and nursing mothers: Use only if the
glaucoma (4.2) potential benefit justifies the potential risk to the fetus or
child. (8.1, 8.3)
-----------------WARNINGS AND PRECAUTIONS-----------------
• Suicidality: Monitor for worsening of depressive See 17 for PATIENT COUNSELING INFORMATION and
symptoms and suicide risk (5.1) Medication Guide.
• Serotonin Syndrome: Serotonin syndrome has been
Revised: March 2009
reported with SNRIs and SSRIs. Concomitant use of
serotonergic drugs is not recommended (5.2)
03/01/09 Page 2
*Sections or subsections omitted from the full prescribing information are not listed.
Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice
daily).
Savella should be tapered and not abruptly discontinued after extended use [see Discontinuing
Savella (2.4) and Warnings and Precautions (5.7)]
Based on individual patient response, the dose may be increased to 100 mg/day (50 mg twice
daily).
Savella is not recommended for patients with end-stage renal disease.
Film-coated, immediate release tablets in four strengths: 12.5 mg, 25 mg, 50 mg, and 100 mg of
milnacipran hydrochloride.
12.5 mg tablets are round, blue, "F" on one side, "L" on the reverse;
25 mg tablets are round, white, "FL" on one side, "25" on the reverse;
50 mg tablets are oval, white, "FL" on one side, "50" on the reverse;
100 mg tablets are oval, pink, "FL" on one side, "100" on the reverse
[see Description (11) and How Supplied/ Storage and Handling (16)].
4 CONTRAINDICATIONS
Patients, both adult and pediatric, with depression or other psychiatric disorders may experience
worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality)
or unusual changes in behavior, whether or not they are taking these medications, and this risk
may persist until significant remission occurs. Suicide is a known risk of depression and certain
other psychiatric disorders, and these disorders themselves are the strongest predictors of
suicide. There has been a long-standing concern, however, that antidepressants, including drugs
that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early
phases of treatment.
In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a
history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients
treated with placebo, 0% in patients treated with Savella 100 mg/day, and 1.3% in patients
treated with Savella 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1
year) fibromyalgia trials.
03/01/09 Page 5
Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs
and others) showed that these drugs increase the risk of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive
disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in
the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a
reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials
of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-
controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-
term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs, but a tendency toward an
increase in the younger patients for almost all drugs studied. There were differences in absolute
risk of suicidality across the different indications, with the highest incidence in MDD. The risk of
differences (drug versus placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of cases of suicidality
per 1000 patients treated) are provided in Table 1.
Table 1. Risk Differences (Drug – Placebo) in the number of Cases of Suicidality, per 1000
patients treated
Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000
Patients Treated
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥ 65 6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or
serotonin for any indication should be monitored appropriately and observed closely for
clinical worsening, suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose changes, either
increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been
reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of
norepinephrine and/or serotonin for major depressive disorder as well as for other indications,
both psychiatric and nonpsychiatric. Although a causal link between the emergence of such
symptoms and either the worsening of depression and/or the emergence of suicidal impulses has
not been established, there is concern that such symptoms may represent precursors to
emerging suicidality.
03/01/09 Page 6
If the decision has been made to discontinue treatment due to worsening depressive symptoms
or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with
recognition that abrupt discontinuation can produce withdrawal symptoms [see
Dosage and Administration—Recommended Dosing (2.1), Dosage—Discontinuing Savella (2.4),
and Warnings and Precautions—Discontinuation of Treatment with Savella (5.7)].
Families and caregivers of patients being treated with drugs inhibiting the reuptake of
norepinephrine and/or serotonin for major depressive disorder or other indications, both
psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for
the emergence of agitation, irritability, unusual changes in behavior, and the other
symptoms described above, as well as the emergence of suicidality, and to report such
symptoms immediately to health care providers. Such monitoring should include daily
observation by families and caregivers. Prescriptions for Savella should be written for the
smallest quantity of tablets consistent with good patient management, in order to reduce
the risk of overdose.
The concomitant use of Savella with MAOIs is contraindicated [see Contraindications (4.1)].
The concomitant use of Savella with serotonin precursors (such as tryptophan) is not
recommended [see Drug Interactions (7)].
In the 3-month placebo-controlled fibromyalgia clinical trials, Savella treatment was associated
with mean increases of up to 3.1 mm Hg in systolic blood pressure (SBP) and diastolic blood
pressure (DBP) [see Adverse Reactions (6.3)].
Among fibromyalgia patients who were hypertensive at baseline, more patients in the Savella
treatment arms had a >15 mmHg increase in SBP than placebo at the end of the study: 1% of
patients in the placebo arm versus 7% in the Savella 100 mg/day and 2% in the Savella 200
mg/day treatment arms. Similarly, more patients who were hypertensive at baseline and were
treated with Savella had DBP increases > 10 mmHg than placebo at the end of study: 3% of
patients in the placebo arm versus 8% in the Savella 100 mg/day and 6% in the Savella 200
mg/day treatment arms.
Sustained increases in blood pressure could have adverse consequences. Cases of elevated
blood pressure requiring immediate treatment have been reported.
Concomitant use of Savella with drugs that increase blood pressure and pulse has not been
evaluated and such combinations should be used with caution [see Drug Interactions (7)].
Effects of Savella on blood pressure in patients with significant hypertension or cardiac disease
have not been systematically evaluated. Savella should be used with caution in these patients.
Blood pressure should be measured prior to initiating treatment and periodically measured
throughout Savella treatment. Pre-existing hypertension and other cardiovascular disease should
be treated before starting therapy with Savella. For patients who experience a sustained increase
in blood pressure while receiving Savella, either dose reduction or discontinuation should be
considered.
In clinical trials, relative to placebo, Savella treatment was associated with mean increases in
pulse rate of approximately 7 to 8 beats per minute [see Adverse Reactions (6.2, 6.3)].
Increases in pulse ≥ 20 bpm occurred more frequently in Savella-treated patients when compared
to placebo: 0.3% in the placebo arm versus 8% in the Savella 100 mg/day and 8% in the 200
03/01/09 Page 8
mg/day treatment arms. The effect of Savella on heart rate did not appear to increase with
increasing dose.
Savella has not been systematically evaluated in patients with a cardiac rhythm disorder.
Heart rate should be measured prior to initiating treatment and periodically measured throughout
Savella treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated
before starting therapy with Savella. For patients who experience a sustained increase in heart
rate while receiving Savella, either dose reduction or discontinuation should be considered.
5.5 Seizures
Savella has not been systematically evaluated in patients with a seizure disorder. In clinical trials
evaluating Savella in patients with fibromyalgia, seizures/convulsions have not been reported.
However, seizures have been reported infrequently in patients treated with Savella for disorders
other than fibromyalgia. Savella should be prescribed with care in patients with a history of a
seizure disorder.
5.6 Hepatotoxicity
In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with
Savella with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were
observed. Increases in ALT were more frequently observed in the patients treated with Savella
100 mg/day (6%) and Savella 200 mg/day (7%), compared to the patients treated with placebo
(3%). One patient receiving Savella 100 mg/day (0.2%) had an increase in ALT greater than 5
times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in
AST were more frequently observed in the patients treated with Savella 100 mg/day (3%) and
Savella 200 mg/day (5%) compared to the patients treated with placebo (2%).
The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant.
No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥
2x ULN.
There have been cases of increased liver enzymes and reports of severe liver injury, including
fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe
liver injury there were significant underlying clinical conditions and/or the use of multiple
concomitant medications. Because of underreporting, it is impossible to provide an accurate
estimate of the true incidence of these reactions.
Savella should be discontinued in patients who develop jaundice or other evidence of liver
dysfunction. Treatment with Savella should not be resumed unless another cause can be
established.
Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of
chronic liver disease.
During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous
reports of adverse events indicative of withdrawal and physical dependence occurring upon
discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events
include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g.,
paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy,
03/01/09 Page 9
emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are
generally self-limiting, some have been reported to be severe.
Patients should be monitored for these symptoms when discontinuing treatment with Savella.
Savella should be tapered and not abruptly discontinued after extended use. If intolerable
symptoms occur following a decrease in the dose or upon discontinuation of treatment, then
resuming the previously prescribed dose may be considered. Subsequently, the physician may
continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.4)].
5.8 Hyponatremia
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. In
many cases, this hyponatremia appears to be the result of the syndrome of inappropriate
antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have
been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs,
SSRIs, or Savella. Also, patients taking diuretics or who are otherwise volume-depleted may be
at greater risk [see Geriatric Use (8.5)]. Discontinuation of Savella should be considered in
patients with symptomatic hyponatremia.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of
Savella and NSAIDs, aspirin, or other drugs that affect coagulation.
Do not use Savella in patients with Uncontrolled Narrow-Angle Glaucoma [see Contraindications
(4.2)].
6 ADVERSE REACTIONS
The stated frequencies of adverse reactions represent the proportion of individuals who
experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction
was considered treatment emergent if it occurred for the first time or worsened while receiving
therapy following baseline evaluation.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
Table 2 lists all adverse reactions that occurred in at least 2% of patients treated with Savella at
either 100 or 200 mg/day and at an incidence greater than that of placebo.
(n = 623) % (n = 934) %
Cardiac Disorders
Palpitations 8 7 7 2
Tachycardia 3 2 2 1
Eye Disorders
Vision blurred 1 2 2 1
Gastrointestinal Disorders
Nausea 35 39 37 20
Constipation 16 15 16 4
Vomiting 6 7 7 2
Dry mouth 5 5 5 2
Abdominal pain 3 3 3 2
General Disorders
Chest pain 3 2 2 2
Chills 1 2 2 0
Chest discomfort 2 1 1 1
Infections
Upper respiratory tract infection 7 6 6 6
Investigations
Heart rate increased 5 6 6 1
Blood pressure increased 3 3 3 1
Metabolism and Nutrition
Disorders
Decreased appetite 1 2 2 0
Nervous System Disorders
Headache 19 17 18 14
Dizziness 11 10 10 6
Migraine 6 4 5 3
Paresthesia 2 3 2 2
Tremor 2 2 2 1
Hypoesthesia 1 2 1 1
Tension headache 2 1 1 1
Psychiatric Disorders
Insomnia 12 12 12 10
Anxiety 5 3 4 4
Respiratory Disorders
Dyspnea 2 2 2 1
Skin Disorders
Hyperhidrosis 8 9 9 2
Rash 3 4 3 2
Pruritus 3 2 2 2
Vascular Disorders
Hot flush 11 12 12 2
Hypertension 7 4 5 2
Flushing 2 3 3 1
Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg
in placebo-treated patients.
6.6 Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia
Following is a list of frequent (those occurring on one or more occasions in at least 1/100
patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated
with Savella for periods up to 68 weeks. The listing does not include those events already listed in
Table 2, those events for which a drug cause was remote, those events which were so general as
to be uninformative, and those events reported only once which did not have a substantial
probability of being acutely life threatening.
Adverse reactions are categorized by body system and listed in order of decreasing frequency.
Adverse reactions of major clinical importance are described in the Warnings and Precautions
section (5).
7 DRUG INTERACTIONS
Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose
excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and
in vivo studies showed that Savella is unlikely to be involved in clinically significant
pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations (12.4)].
8.1 Pregnancy
Pregnancy Category C
Milnacipran increased the incidence of dead fetuses in utero in rats at doses of 5 mg/kg/day (0.25
times the MRHD on a mg/m2 basis). Administration of milnacipran to mice and rabbits during the
period of organogenesis did not result in embryotoxicity or teratogenicity at doses up to 125
mg/kg/day in mice (3 times the maximum recommended human dose [MRHD] of 200 mg/day on
a mg/m2 basis) and up to 60 mg/kg/day in rabbits (6 times the MRHD of 200 mg/day on a mg m2
basis). In rabbits, the incidence of the skeletal variation, extra single rib, was increased following
administration of milnacipran at 15 mg/kg/day during the period of organogenesis.
There are no adequate and well-controlled studies in pregnant women. Savella should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective
serotonin reuptake inhibitors late in the third trimester have developed complications requiring
prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise
03/01/09 Page 14
immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis,
apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia,
hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are
consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug
discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent
with serotonin syndrome [see Warnings and Precautions (5.2)].
In rats, a decrease in pup body weight and viability on postpartum day 4 were observed when
milnacipran, at a dose of 5 mg/kg/day (approximately 0.2 times the MRHD on a mg/m2 basis),
was administered orally to rats during late gestation. The no-effect dose for maternal and
offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m2 basis).
SNRIs, SSRIs, and Savella, have been associated with cases of clinically significant
hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings
and Precautions (5.8)].
9.2 Abuse
Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human
studies.
9.3 Dependence
Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal
symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal
03/01/09 Page 15
symptoms can be severe. Thus, Savella should be tapered and not abruptly discontinued after
extended use. [see Section 5.7 Discontinuation of Treatment with Savella].
10 OVERDOSAGE
There is limited clinical experience with Savella overdose in humans. In clinical trials, cases of
acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with
none being fatal.
In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily
involving multiple drugs but also with Savella only. The most common signs and symptoms
included increased blood pressure, cardio-respiratory arrest, changes in the level of
consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased
hepatic enzymes.
Management of Overdose
There is no specific antidote to Savella, but if serotonin syndrome ensues, specific treatment
(such as with cyproheptadine and/or temperature control) may be considered. In case of acute
overdose, treatment should consist of those general measures employed in the management of
overdose with any drug.
An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital
signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-
bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed
soon after ingestion or in symptomatic patients. Because there is no specific antidote for
Savella, symptomatic care and treatment with gastric lavage and activated charcoal should be
considered as soon as possible for patients who experience a Savella overdose.
Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and
exchange transfusion are unlikely to be beneficial.
In managing overdose, the possibility of multiple drug involvement should be considered. The
physician should consider contacting a poison control center for additional information on the
treatment of any overdose. Telephone numbers for certified poison control centers are listed in
the Physicians’ Desk Reference (PDR).
11 DESCRIPTION
Milnacipran hydrochloride is a selective norepinephrine and serotonin reuptake
inhibitor; it inhibits norepinephrine uptake with greater potency than serotonin. It is a
racemic mixture with the chemical name: (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-
phenylcyclopropanecarboxamide hydrochloride. The structural formula is:
O NH2 . HCl
N
03/01/09 Page 16
Milnacipran hydrochloride is a white to off-white crystalline powder with a melting point of 179°C.
It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly
soluble in diethyl ether. It has an empirical formula of C15H23ClN2O and a molecular weight of
282.8 g/mol.
Savella is available for oral administration as film-coated tablets containing 12.5 mg, 25 mg, 50
mg, and 100 mg milnacipran hydrochloride. Each tablet also contains dibasic calcium phosphate,
povidone, carboxymethylcellulose calcium, colloidal silicon dioxide, magnesium stearate, and talc
as inactive ingredients. Additionally, the following inactive ingredients are also present as
components of the film coat:
12.5 mg:
FD&C Blue #2 Aluminum Lake, hypromellose, polyethylene glycol, titanium dioxide
25 mg:
Hypromellose, polyethylene glycol, titanium dioxide
50 mg:
Hypromellose, polyethylene glycol, titanium dioxide
100 mg:
FD&C Red #40 Aluminum Lake, hypromellose, polyethylene glycol, titanium dioxide
12 CLINICAL PHARMACOLOGY
12.2 Pharmacodynamics
Cardiovascular Electrophysiology―The effect of Savella on the QTcF interval was measured in a
double-blind placebo- and positive-controlled parallel study in 88 healthy subjects using 600
mg/day Savella (3 to 6 times the recommended therapeutic dose for fibromyalgia). After baseline
and placebo adjustment, the maximum mean QTcF change was 8 ms (2-sided 90% CI, 3 - 12
ms). This increase is not considered to be clinically significant.
12.3 Pharmacokinetics
Milnacipran is well absorbed after oral administration with an absolute bioavailability of
approximately 85% to 90%. The exposure to milnacipran increased proportionally within the
therapeutic dose range. It is excreted predominantly unchanged in urine (55%) and has a
terminal elimination half-life of about 6 to 8 hours. Steady-state levels are reached within 36 to 48
hours and can be predicted from single-dose data. The active enantiomer, d-milnacipran, has a
longer elimination half-life (8-10 hours) than the l-enantiomer (4-6 hours). There is no
interconversion between the enantiomers.
No dosage adjustment is necessary for patients with mild renal impairment. Caution should be
exercised in patients with moderate renal impairment. Dose adjustment is necessary in severe
renal impairment patients. [see Dosage and Administration (2.2)].
Elderly―Cmax and AUC parameters of milnacipran were about 30% higher in elderly (> 65
years) subjects compared with young subjects due to age-related decreases in renal function.
No dosage adjustment is necessary based on age unless renal function is severely impaired [see
Dosage and Administration (2.2)].
Gender―Cmax and AUC parameters of milnacipran were about 20% higher in female subjects
compared with male subjects. Dosage adjustment based on gender is not necessary.
Drug-Drug Interactions
In Vitro Studies
In general, milnacipran, at concentrations that were at least 25 times those attained in clinical
trials, did not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
CYP3A4 or induce human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5
enzyme systems, indicating a low potential of interactions with drugs metabolized by these
enzymes.
In vitro studies have shown that the biotransformation rate of milnacipran by human hepatic
microsomes and hepatocytes was low. A low biotransformation was also observed following
incubation of milnacipran with cDNA-expressed human CYP1A2, CYP2A6, CYP2B6, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isozymes.
03/01/09 Page 18
In Vivo Studies
The drug interaction studies described in this section were conducted in healthy adult subjects.
Digoxin―There was no pharmacokinetic interaction between Savella (200 mg/day) and digoxin
(0.2 mg/day Lanoxicaps) following multiple-dose administration to healthy subjects.
Fluoxetine―Switch from fluoxetine (20 mg once a day), a strong inhibitor of CYP2D6 and a
moderate inhibitor of CYP2C19, to milnacipran (100 mg/day) without a washout period did not
affect the pharmacokinetics of milnacipran.
Lithium―Multiple doses of Savella (100 mg/day) did not affect the pharmacokinetics of lithium.
Lorazepam―There was no pharmacokinetic interaction between a single dose of Savella (50 mg)
and lorazepam (1.5 mg).
13 NONCLINICAL TOXICOLOGY
Mutagenesis
Milnacipran was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or in
the L5178Y TK +/- mouse lymphoma forward mutation assay. Milnacipran was also not
clastogenic in an in vitro chromosomal aberration test in human lymphocytes or in the in vivo
mouse micronucleus assay.
Impairment of Fertility
Although administration of milnacipran to male and female rats had no statistically significant
effect on mating or fertility at doses up to 80 mg/kg/day (4 times the MRHD on an mg/m2 basis)
there was an apparent dose-related decrease in the fertility index at clinically relevant doses
based on body surface area.
03/01/09 Page 19
Ocular Effects
Chronic (2-years) administration of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on a
mg/m2 basis) and higher doses showed increased incidence of keratitis of the eye. One year
studies in the rat and primate did not show this response.
14 CLINICAL STUDIES
Management of Fibromyalgia
The efficacy of Savella for the management of fibromyalgia was established in two double-blind,
placebo-controlled, multicenter studies in adult patients (18-74 years of age). Enrolled patients
met the American College of Rheumatology (ACR) criteria for fibromyalgia (a history of
widespread pain for 3 months and pain present at 11 or more of the 18 specific tender point
sites). Approximately 35% of patients had a history of depression. Study 1 was six months in
duration and Study 2 was three months in duration.
A larger proportion of patients treated with Savella than with placebo experienced a simultaneous
reduction in pain from baseline of at least 30% (VAS) and also rated themselves as much
improved or very much improved based on the patient global assessment (PGIC). In addition, a
larger proportion of patients treated with Savella met the criteria for treatment response, as
measured by the composite endpoint that concurrently evaluated improvement in pain (VAS),
physical function (SF-36 PCS), and patient global assessment (PGIC), in fibromyalgia as
compared to placebo.
Study 1: This 6-month study compared total daily doses of Savella 100 mg and 200 mg to
placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 50 mm on a 100
mm visual analog scale (VAS) ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean
baseline pain score in this trial was 69. The efficacy results for Study 1 are summarized in Figure
1.
Figure 1 shows the proportion of patients achieving various degrees of improvement in pain from
baseline to the 3-month time point and who concurrently rated themselves globally improved
(PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned
0% improvement. More patients in the Savella treatment arms experienced at least a 30%
reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than
did patients in the placebo arm. Treatment with Savella 200 mg/day did not confer greater benefit
than treatment with Savella 100 mg/day.
Figure 1: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being
Much or Very Much Improved on the PGIC ― Study 1
03/01/09 Page 20
Study 2: This 3-month study compared total daily doses of Savella 100 mg and 200 mg to
placebo. Patients were enrolled with a minimum mean baseline pain score of ≥ 40 mm on a 100-
mm VAS ranging from 0 (“no pain”) to 100 (“worst possible pain”). The mean baseline pain score
in this trial was 65. The efficacy results for Study 2 are summarized in Figure 2.
Figure 2 shows the proportion of patients achieving various degrees of improvement in pain from
baseline to the 3-month time point and who concurrently rated themselves globally improved
(PGIC score of 1 or 2). Patients who did not complete the 3-month assessment were assigned
0% improvement. More patients in the Savella treatment arms experienced at least a 30%
reduction in pain from baseline (VAS) and considered themselves globally improved (PGIC) than
did patients in the placebo arm. Treatment with Savella 200 mg/day did not confer greater benefit
than treatment with Savella 100 mg/day.
Figure 2: Patients Achieving Various Levels of Pain Relief with Concurrent Ratings of Being
Much or Very Much Improved on the PGIC ― Study 2
03/01/09 Page 21
In both studies, some patients who rated themselves as globally “much” or “very much” improved
experienced a decrease in pain as early as week 1 of treatment with a stable dose of Savella that
persisted throughout these studies.
12.5-mg tablets:
Blue, round, film-coated tablets, debossed with “F” on one side and “L” on the reverse
Bottles of 60: NDC 0456-1512-60
25-mg tablets:
White, round, film-coated tablets, debossed with “FL” on one side and “25” on the reverse
Bottles of 60: NDC 0456-1525-60
Bottles of 180: NDC 0456-1525-01
50-mg tablets:
White, oval-shaped, film-coated tablets, debossed with “FL” on one side and “50” on the reverse
Bottles of 60: NDC 0456-1550-60
Bottles of 180: NDC 0456-1550-01
100-mg tablets:
Pink, oval-shaped film-coated tablets, debossed with “FL” on one side and “100” on the reverse
Bottles of 60: NDC 0456-1510-60
Bottles of 180: NDC 0456-1510-01
03/01/09 Page 22
Titration Pack:
4-Week Titration Pack: NDC 0456-1500-55
Blister package containing 55 tablets: 5 x 12.5-mg tablets, 8 x 25-mg tablets, and 42 x 50 mg
tablets.
Storage
Store at 25°C (77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F)
[See USP Controlled Room Temperature].
Patients should be advised of the following issues and asked to alert their prescriber if these
occur while taking Savella:
Patients, their families and their caregivers should be encouraged to be alert to the emergence of
anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,
akathisia (psychomotor restlessness), hypomania or other unusual changes in behavior,
worsening of depression, and suicidal ideation, especially early during treatment with Savella or
other drugs that inhibit the reuptake of norepinephrine and/or serotonin, and when the dose is
adjusted up or down. Families and caregivers of patients should be advised to observe for the
emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient’s prescriber or health professional, especially if they
are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. [see Box
Warning and Warnings and Precautions (5.1)].
Patients should be cautioned about the concomitant use of Savella and NSAIDs, aspirin, or other
drugs that affect coagulation, since the combined use of agents that interfere with serotonin
reuptake and these agents has been associated with an increased risk of abnormal bleeding [see
Warnings and Precautions (5.9)].
17.7 Alcohol
Patients should be advised to avoid consumption of alcohol while taking Savella [see Warnings
and Precautions (5.6, 5.13)].
17.8 Discontinuation
Patients should be advised that withdrawal symptoms can occur when discontinuing treatment
with Savella, particularly when discontinuation is abrupt. [see Warnings and Precautions (5.7)]
17.9 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become
pregnant during Savella therapy [see Use in Specific Populations (8.1)].
17.10 Nursing
Patients should be advised to notify their physician if they are breast-feeding [see Use in Specific
Populations (8.3)].
MEDICATION GUIDE
Savella (Sa-vel-la) Tablets
(milnacipran HCl)
Antidepressant Medicines, Depression and other serious Mental Illnesses, and Suicidal
Thoughts or Actions
Savella is not used to treat depression, but it acts like medicines that are used to treat depression
(antidepressants) and other psychiatric disorders.
Read the Medication Guide that comes with you or your family member’s antidepressant
medicine. This Medication Guide is only about the risk of suicidal thoughts or actions with
antidepressant medicines. Talk to your or your family member’s healthcare provider about:
• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?
history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or
actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a
family member?
• Pay close attention to any changes, especially sudden changes, in mood,
behaviors, thoughts, or feelings. This is very important when an antidepressant
medicine is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in
mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the
healthcare provider between visits as needed, especially if you have concerns
about symptoms.
Call a healthcare provider right away if you or your family member has any of the following
symptoms, especially if they are new, worse, or worry you:
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Forest Pharmaceuticals, Inc.
Manufactured by:
Forest Laboratories, Inc.